CN1761465B - Method for preparing coating preparation - Google Patents

Abstract

The present invention aims to provide a method for preparing a formulation coated with pioglitazone hydrochloride, the formulation being used as a therapeutic agent for diabetes, etc., and having excellent formulation properties, such as the excellent elution properties of pioglitazone hydrochloride.

Description

Method for preparing coating preparation

technical field

The present invention relates to a method for producing a preparation coated with pioglitazone hydrochloride, which is used as a therapeutic agent for diabetes and the like.

Background technique

The following is a report on a pharmaceutical composition comprising an insulin sensitizer such as a thiazolidinedione compound and a biguanide.

1) A pharmaceutical agent has been reported (see EP-749751A) containing an insulin sensitizer combined with at least one of the following ingredients: an α-glucosidase inhibitor, an aldose reductase inhibitor, Biguanides, statin compounds, squalene synthesis inhibitors, fibrate compounds, LDL catabolic enhancers and angiotensin converting enzyme inhibitors.

2) A pharmaceutical composition was reported (see WO98/57634) comprising an insulin sensitizer, a biguanide, an antihyperglycemic agent and a pharmaceutically acceptable carrier.

3) A pharmaceutical composition was reported (see WO01/35940) comprising thiazolidinedione, metformin hydrochloride (metformin hydrochloride) and a pharmaceutically acceptable carrier, wherein thiazolidinedione was formulated on the surface of metformin hydrochloride.

4) A pharmaceutical composition (see WO01/35941) comprising thiazolidinedione, metformin hydrochloride and their own pharmaceutically acceptable carrier, wherein thiazolidinedione and metformin hydrochloride are respectively dispersed in the pharmaceutically acceptable carrier middle.

5) A core formulation (see WO01/82875) was reported (see WO01/82875) comprising (a) a first layer containing pioglitazone hydrochloride or a pharmaceutically acceptable salt thereof as an active ingredient, and (b) containing a biguanide As the core of the active ingredient, at least a part of the core is enclosed by the first layer.

6) A core preparation is reported (see USP6403121) comprising a first layer containing pioglitazone hydrochloride, the first layer covering at least a part of the core containing biguanide, wherein one or both of the core and the first layer Dispersed in modulating release agent (modulating release agent) such as polysaccharide, etc.

Contents of the invention

The object of the present invention is to provide a preparation method of a preparation coated with pioglitazone hydrochloride, which can be used as a therapeutic agent for diabetes, etc., and has excellent storage stability, and the characteristics of the preparation are such as the dissolution properties of pioglitazone hydrochloride. ) with excellent performance.

The present inventors have found that, in the preparation of formulations coated with pioglitazone hydrochloride, the dissolution properties of pioglitazone hydrochloride (especially Dissolution performance within 15 minutes from dissolution test) Excellent coated preparation. The present inventors also conducted further studies based on this finding, and thus completed the present invention.

Therefore, the present invention involves

1) the preparation method of coating preparation, it comprises coating with the aqueous dispersion of the pioglitazone hydrochloride that comprises low-viscosity coating material;

2) the coating preparation obtained by the preparation method of the above 1);

3) The preparation method of the above 1), wherein the viscosity of the 5% aqueous solution of the low-viscosity coating material is not greater than 35mPa·s at 20°C;

4) The preparation method of the above-mentioned 1), wherein the low-viscosity coating material is hydroxypropyl cellulose SL, hydroxypropyl cellulose SSL or polyvinyl alcohol-polyethylene glycol graft copolymer;

5) The production method of 1) above, wherein the core comprising the active ingredient is coated with an aqueous dispersion of pioglitazone hydrochloride comprising a low-viscosity coating material;

6) The preparation method of the above-mentioned 5), wherein the active ingredient is a therapeutic agent for diabetes;

7) The preparation method of the above 6), wherein the therapeutic agent for diabetes is biguanide;

8) The preparation method of the above 7), wherein the biguanide is metformin hydrochloride;

9) The preparation method of the above-mentioned 5), wherein the active ingredient is a therapeutic agent for hyperlipidemia;

10) The production method of 9) above, wherein the therapeutic agent for hyperlipidemia is an HMG-CoA reductase inhibitor;

11) A method for improving pioglitazone hydrochloride dissolution from a preparation coated with pioglitazone hydrochloride, comprising coating with an aqueous dispersion of pioglitazone hydrochloride comprising a low-viscosity coating material when preparing the preparation;

12) A coated preparation obtained by the production method of 1) above, which releases not less than 50% of pioglitazone hydrochloride within 15 minutes in a dissolution test using hydrochloric acid as a test solution at 37° C. and 100 rpm - Potassium chloride buffer (pH 2.0) by basket method (basket method);

13) A coated preparation obtained by the production method of 1) above, which releases not less than 50% of pioglitazone hydrochloride within 15 minutes in a dissolution test using hydrochloric acid as a test solution at 37° C. and 50 rpm - Potassium chloride buffer (pH 2.0) by paddle method; etc.

The average particle size of pioglitazone hydrochloride used in the present invention is preferably 0.5-500 μm, more preferably 1-150 μm.

The aqueous dispersion used in the present invention may be an aqueous solution or an aqueous suspension.

The concentration of pioglitazone hydrochloride in the aqueous dispersion is, for example, 1-25% (W/W), preferably 1-15% (W/W). Concentrations in these ranges are preferable from the viewpoints of coating workability, content uniformity of pioglitazone hydrochloride in the obtained coating preparation, and the like.

The "aqueous dispersion of pioglitazone hydrochloride" (hereinafter sometimes simply referred to as the dispersion of the present invention) includes a low-viscosity coating material.

As used herein, "low-viscosity coating material" means, for example, that the viscosity of its 5% (W/V) aqueous solution is not greater than 35 mPa·s (preferably not greater than 30 mPa·s, more preferably not greater than 25 mPa·s) at 20°C. s) Coating material. When the concentration of the coating material in the aqueous solution, measurement conditions (such as measurement temperature), etc. are different, the viscosity of the coating material also changes. When the measurement conditions are different, coating materials having a viscosity value converted to the viscosity of a 20°C, 5% (W/V) aqueous solution within the above-mentioned viscosity range are included in the "low-viscosity coating material" of the present invention.

As the "low-viscosity coating material", there can be mentioned, for example, hydroxypropylcellulose (grade: SL, SSL (trademark); Nippon Soda Co., Ltd.), hydroxypropylmethylcellulose (grade: MW, E, EW (trademark); Shin-Etsu Chemical Co., Ltd.) (grade: E-3 (trademark); Nippon Soda Co., Ltd.), hydroxypropyl cellulose (grade: SSL, Nippon Soda Co. , Ltd.) and hydroxypropyl methylcellulose (grade: E-3) premix (grade: SSM (trademark), Nippon Soda Co., Ltd.), polyvinyl alcohol-polyethylene glycol graft Copolymer (Kollicoat IR (trademark), BAS F, Germany) and the like.

The above-mentioned coating material may be a mixture of two or more kinds in an appropriate ratio. When the coating material mixture obtained by mixing one or more selected from the above-mentioned coating materials with one or more high-viscosity coating materials in an appropriate ratio is "a 5% (W/V) aqueous solution thereof When the viscosity is not more than 35 mPa·s at 20° C., the mixture can be used as the “low-viscosity coating material” of the present invention. As used herein, "high viscosity coating material" means, for example, a coating material whose viscosity as a 5% (W/V) aqueous solution is greater than 35 mPa·s at 20°C. Specific examples thereof include hydroxypropylcellulose (grade: L (trademark); Nippon Soda Co., Ltd.) (grades: Klucel EF, Klucel LF (trademark); Aqualon (USA)), hydroxypropylmethylcellulose element (grade: R (trademark); Shin-Etsu Chemical Co., Ltd.), and the like.

The low-viscosity coating material preferably includes hydroxypropyl cellulose SL (viscosity of 5% aqueous solution at 20°C: about 24mPa·s; and/or viscosity of 2% aqueous solution at 20°C: 3.0-5.9mPa·s ), hydroxypropylcellulose SSL (viscosity of 5% aqueous solution at 20°C: about 8mPa·s; and/or viscosity of 2% aqueous solution at 20°C: 2.0-2.9mPa·s), polyvinyl alcohol - Polyethylene glycol graft copolymer [Kollicoat IR (trademark), BASF, Germany] (viscosity of 5% aqueous solution at 20° C.: about 18 mPa·s) and the like.

Low viscosity coating materials can be dissolved or suspended in the dispersions of the invention. In order to efficiently prepare a coated formulation excellent in content uniformity of pioglitazone hydrochloride and formulation strength, it is preferable to dissolve the coating material in the dispersion of the present invention.

The dispersions of the invention may also contain coating additives. As paint additives, mention may be made, for example, of shading agents and/or colorants such as titanium dioxide (titanium oxide), talc, iron oxide, etc.; plasticizers such as polyethylene glycol, triethyl citrate, castor oil, Polysorbate, etc.; organic acids such as citric acid, tartaric acid, malic acid, ascorbic acid, etc.; lactose, D-mannitol, low-substituted hydroxypropyl cellulose, carmellose calcium, crospovidone, etc.

When the paint additive is water-insoluble, its average particle size is preferably not greater than 500 μm, more preferably not greater than 150 μm, especially preferably not greater than 75 μm. When the coating additive having the average particle size is used, a coated formulation excellent in the content uniformity of pioglitazone hydrochloride and the strength of the formulation can be effectively obtained.

The concentration of the low-viscosity coating material in the dispersion of the invention is, for example, 1-30% (W/W), preferably 1-25% (W/W), more preferably 2-25% (W/W). Concentrations in these ranges are preferable in consideration of the workability of coating, the uniformity of the content of pioglitazone hydrochloride in the obtained coating preparation, and the like.

The concentration of coating additives in the dispersion of the invention is, for example, 0.2-35% (W/W), preferably 0.2-30% (W/W), more preferably 0.5-15% (W/W). Concentrations in these ranges are preferable in consideration of the workability of coating, the uniformity of the content of pioglitazone hydrochloride in the obtained coating preparation, and the like.

As the core to be coated with an aqueous dispersion of pioglitazone hydrochloride comprising a low-viscosity coating material (hereinafter sometimes referred to as the core of the present invention), for example, solid preparations such as tablets, capsules, granules, powders, lozenges can be mentioned (troche) and so on. The solid preparation may be a controlled release preparation such as an immediate release preparation, a sustained release preparation (sustained release preparation) and the like. Solid preparations may contain conventional additives in the field of pharmaceutical preparations, and may also be prepared according to known methods. As additives, for example, mention may be made of: excipients, disintegrants, binders, lubricants, colorants, pH regulators, surfactants, release-sustaining agents, stabilizers, sour agents (sour agent), flavoring agent, glidant, etc. These additives are used in amounts customary in the field of pharmaceutical preparations.

As excipients, for example, there may be mentioned: starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, porous (porous) starch, etc.; sugar and sugar Alcohols such as lactose, fructose, glucose, D-mannitol, sorbitol, etc.; anhydrous calcium phosphate, crystalline cellulose, precipitated calcium carbonate, calcium silicate, etc.

As the disintegrant, for example, carboxymethyl cellulose, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, Hydroxypropyl starch, etc. The used amount of the disintegrant is preferably 0.5-25 parts by weight, more preferably 1-15 parts by weight, per 100 parts by weight of the solid preparation.

As the binder, for example, there may be mentioned: crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gum arabic powder, and the like. The binder is used in an amount of preferably 0.1-50 parts by weight, more preferably 0.5-40 parts by weight per 100 parts by weight of the solid preparation.

Preferable examples of lubricants include magnesium stearate, calcium stearate, talc, sucrose esters of fatty acids, sodium stearyl fumarate, and the like.

As the coloring agent, for example, food colorings such as Food Yellow No. 5, Food Red No. 2, Food Blue No. 2 and the like, food lake colors, iron oxide and the like can be mentioned.

As the pH adjuster, citrates, phosphates, carbonates, tartrates, fumarates, acetates, amino acid salts and the like can be mentioned.

As the surfactant, sodium stearyl sulfate, Tween 80, polyoxyethylene (160) polyoxypropylene (30) glycol (polyoxyethylene (160) polyoxypropylene (30) glycol) and the like can be mentioned.

As the release sustaining agent, for example, cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose (preferably hydroxypropylmethylcellulose 2910, hydroxypropylmethylcellulose 2208, etc.) can be mentioned , cellulose acetate (preferably cellulose acetate with an acetyl content of 39.3-40%), cellulose diacetate, cellulose triacetate, cellulose acetate propionate, ethyl cellulose, sodium carboxymethyl cellulose, crystalline fiber sodium alginate, carboxymethyl cellulose, etc.; sodium alginate, carboxyvinyl polymer; acrylic polymers such as aminoalkyl methacrylate copolymer RS (Eudragit RS (trademark), Rohm Pharma), ethyl acrylate- Methyl methacrylate copolymer suspension (Eudragit NE (trademark), Rohm Pharma) and the like. The release sustaining agent may comprise, for example, a flux enhancer (e.g., sodium chloride, potassium chloride, sucrose, sorbitol, D-mannitol, polyethylene glycol (preferably polyethylene glycol 400, etc.) , propylene glycol, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, polyvinyl alcohol, methacrylic acid polymer); plasticizer (e.g. glyceryl acetate, acetylated monoglycerides, grapeseed oil, olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerin sorbitol, oxalic acid Diethyl ester, diethyl maleate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, dibutyl sebacate, triethyl citrate esters, tributyl citrate, tributyrin), etc. Preferable examples of the release sustaining agent include: (1) half-parts containing cellulose acetate (preferably cellulose acetate having an acetyl content of 39.3-40%), polyethylene glycol (preferably polyethylene glycol 400, etc.) and glycerol acetate Transmembrane coatings; (2) sustained-release compositions containing sodium carboxymethylcellulose, hydroxypropylmethylcellulose 2910, hydroxypropylmethylcellulose 2208, and microcrystalline cellulose; and the like.

As the stabilizer, for example, there may be mentioned: tocopherol, sodium edetate, nicotinamide, cyclodextrin and the like.

As the acidifying agent, for example, there may be mentioned: ascorbic acid, citric acid, tartaric acid, malic acid and the like.

As the sour agent, for example, there may be mentioned: menthol, peppermint oil, lemon oil, vanillin and the like.

As the glidant, for example, light anhydrous silicic acid, hydrated silicon dioxide and the like can be mentioned.

The above-mentioned additives may be used in the form of a mixture of two or more kinds in a suitable ratio.

The core of the present invention preferably contains an active ingredient. As used herein, mention may be made of active ingredients: therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, antihypertensive agents, antiobesity agents, diuretics, antithrombotic agents wait. These active agents can be low molecular weight compounds, high molecular weight proteins, polypeptides or antibodies, vaccines and the like. The active ingredient may be a mixture of two or more components in suitable ratios.

The core containing the active ingredient is used as the core of the present invention in this way to provide excellent effects such as: 1) improving the effect of pioglitazone hydrochloride or the active ingredient (synergistic effect on the action of the agent), 2) reducing the activity of pioglitazone hydrochloride or The dosage of the ingredients (compared with the effect of reducing the dosage of the drug with the administration of a single drug), 3) reduces the side effects of pioglitazone hydrochloride or the active ingredient (such as weight gain, ketosis, acidosis), and the like.

Examples of therapeutic agents for diabetes include: insulin preparations (such as animal insulin preparations extracted from the pancreas of cattle and pigs; human insulin preparations synthesized by genetic engineering techniques using E. coli or yeast; zinc insulin; protamine zinc insulin, insulin fragments or derivatives (such as INS-1, etc.), etc.), insulin sensitizers (such as pioglitazone or its salt (preferably hydrochloride), rosiglitazone (rosiglitazone) and its salt (preferably maleate), GI-262570, reglixane (JTT-501), netoglitazone (MCC-555), YM-440, KRP-297, CS-011, FK-614, compounds described in WO99/58510 (such as (E)-4-[ 4-(5-Methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutanoic acid), ragaglitazar (NN-622), tesaglitazar (AZ-242) , BMS-298585, ONO-5816, LM-4156, BM-13-1258, MBX-102, GW-1536, LY-519818, etc.), α-glucosidase inhibitors (such as voribose, acarbose Sugar, miglitol, emiglitate, etc.), biguanides (such as phenformin, metformin, buformin, or salts thereof (such as hydrochloride, fumarate, succinate, etc.) , insulin secretagogues (sulfonylureas (such as tolbutamide, glyburide, dicyclamide, chlorpropamide, tolazamide, glipizide, glimepiride, glipizide , Glipinazole, etc.), repaglinide, nateglinide, mitiglinide or its calcium salt hydrate, GLP-1, etc.), dipeptidylpeptidase (dipeptidylpeptidase) IV inhibition Agents (such as NVP-DPP-278, PT-100, NVP-DDP-728, LAF237, etc.), β3 agonists (such as CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ -9677, BMS-196085, AZ-40140, etc.), dextrin agonists (such as pramlintide, etc.), phosphotyrosine phosphatase inhibitors (such as sodium vanadate, etc.), gluconeogenesis inhibitors (such as sugar Prophosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, etc.) and SGLUT (sodium-glucose cotransporter) inhibitors (such as T-1095, etc.).

溴化物(N-phenacylthiazolium bromide)(ALT766)，EXO-226等)，活性氧净化剂(如硫辛酸等)和脑血管扩张剂(如硫必利，美西律等)。Examples of therapeutic agents for diabetic complications include aldose reductase inhibitors (such as torerestat, epalrestat, zenastat, zopolrestat, minalrestat, fidarestat ) (SNK-860), CT-112, etc.), neurotrophic factors (such as NGF, NT-3, BDNF, etc.), neurotrophin production-secretion enhancers [as described in WO01/14372 Neurotrophin production- Neurotrophin production-secretion promoters (such as 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-(3-(2-methylphenoxy) Propyl)oxazole, etc.)], PKC inhibitors (such as LY-333531, etc.), AGE inhibitors (such as ALT946, pimazidine, pyratoxanthine, N-benzoylthiazole

Bromide (N-phenacylthiazolium bromide) (ALT766), EXO-226, etc.), active oxygen scavengers (such as lipoic acid, etc.) and cerebral vasodilators (such as tiapride, mexiletine, etc.).

Examples of therapeutic agents for hyperlipidemia include HMG-CoA reductase inhibitors (such as pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, fenofibrate, cerivastatin, ethanol Tavastatin (itavastatin), rosuvastatin (rosuvastatin) (ZD-4522), or their salts (such as sodium salt, calcium salt, etc.), etc.), fibrate compounds (such as Special, benzclofibrate, binifibrate, cyprofibrate, clofibrate, clofibrate, clofibrate, etofibrate, fenofibrate, gemfibrozil, nicobibrate, pirifibrate , chlorocigarette fibrate, double fibrate, ethyphylline, clofibrate, etc.), (squalene) synthase inhibitors (such as compounds described in WO97/10224 (such as 1-[[(3R, 5S)-1 -(3-Acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5- Tetrahydro-4,1-benzooxazepin-3-yl]acetyl]piperidine-4-acetic acid (1-[[(3R,5S)-1-(3-acetyl-2,2-dimethylpropyl)-7-chloro -5-(2,3-dimethoxy-phenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzooxazepin-3-yl]acetyl]piperidine-4-acetic acid), etc.), ACAT inhibitors (e.g., Avasimibe, Eflucimibe, etc.), anion exchange resins (e.g., cholestyramine, etc.), probucol, niacin drugs (e.g., Nicomol, Penetral, etc.), eicosapentaenoic acid Ethyl icosapentate, plant sterols (such as soybean sterol, γ-oryzanol (alcohol), etc.), etc.

Examples of antihypertensive agents include: angiotensin-converting enzyme inhibitors (such as captopril, enalapril, delapril, etc.), angiotensin II antagonists (such as candesartan cilexate, Losartan, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, etc.), calcium antagonists (such as manidipine, nifedipine, nicardipine, Amlodipine, Efodi, etc.), potassium channel openers (openers) (such as levochromaline, L-27152, AL 0671, NIP-121, etc.), clonidine, etc.

Examples of anti-obesity agents include: anti-obesity agents acting on the central nervous system (e.g., dexfenfluramine, fenfluramine, phentermine, sibutramine, dipropion, dextroamphetamine, Ming, mazindol, phenylpropanolamine, clobenzylrex, etc.), pancreatic lipase inhibitors (such as orlistat, etc.), β3 agonists (such as CL-316243, SR-58611-A, UL-TG -307, SB-226552, AJ-9677, BMS-196085, AZ-40140, etc.), peptidic anorexiants (such as leptin, CNTF (cilia neurotrophic factor), etc.), cholecystokinin agonist agents (such as lintitript (lintitript), FPL-15849, etc.), and the like.

Examples of diuretics include: xanthine derivatives (such as sodium salicylate and theobromine, calcium salicylate and theobromine, etc.), thiazide agents (such as ethylthiazide, cyclopenthiazine, trichloromethylthiazide (trichloromethyazide, dihydrochlorothiazide, hydrofluorothiazide, benzylhydrochlorothiazide, penfluthiazide, polythiazide, methylchlorothiazide, etc.), antialdosterone (antialdosterone) preparations (such as spironolactone, triaminopterin, etc.), Carbonate dehydratase inhibitors (such as acetazolamide, etc.), chlorobenzenesulfonamide preparations (such as chlorthalidone, mefucilide, indapamide, etc.), azosemide, isosorbide, diuric acid , piretanide, bumetanide, diuretic, etc.

Examples of antithrombotic agents include: heparin (such as heparin sodium, heparin calcium, daltparin sodium, etc.), warfarin (such as warfarin potassium, etc.), antithrombin drugs (such as aragatroban, etc.) , thrombolytic agents (such as urokinase, tisokinase, tissue plasminogen activator, nateplase, monteplase, pamiteplase, etc.) , platelet aggregation inhibitors (such as ticlopidine hydrochloride, cilostazol, ethyl eicosapentaenoate, beraprost sodium, sargrel hydrochloride, etc.), and so on.

The active ingredient is preferably a therapeutic agent for diabetes, more preferably biguanide, especially metformin or a salt thereof (preferably metformin hydrochloride).

In addition, a therapeutic agent for hyperlipidemia is also preferred as an active ingredient. More preferably, the therapeutic agent for hyperlipidemia is an HMG-CoA reductase inhibitor. In particular, simvastatin and the like are preferable.

The amount of the active ingredient in the core of the present invention is, for example, 0.1-100 parts by weight, preferably 1-99 parts by weight, per 100 parts by weight of the core of the present invention.

The core of the present invention is preferably a tablet containing an active ingredient (preferably a therapeutic agent for diabetes, more preferably a biguanide, especially preferably metformin hydrochloride). The shape of the tablet may be round, caplet, oval and the like. Tablets can be prepared, for example, by mixing or granulating the above-mentioned additives and active ingredients according to conventional methods employed in the field of pharmaceutical preparations, and then compress-molding the resulting mixture or granules after mixing.

Here, mixing is performed by, for example, a mixer such as a V-type mixer, a drum mixer, etc., and granulation is performed using, for example, a high-speed mixing granulator, a fluidized bed granulator, and the like. For compression molding, punching is usually performed under a pressure of 5 to 35 kN/cm ² using a single punch tableting machine, a rotary tableting machine, or the like.

When the active ingredient contained in the core of the present invention is not a drug administered once a day (for example, a drug administered twice or three times a day), the core containing the active ingredient is preferably a sustained-release preparation.

When the compatibility of pioglitazone hydrochloride and the active ingredient contained in the core of the present invention is poor, the active ingredient-containing core may be coated with the above-mentioned coating material or the like.

The core of the present invention is more preferably a sustained release formulation (preferably a tablet) comprising a biguanide, preferably metformin hydrochloride. As such preparations, for example, controlled-release pharmaceutical tablets described in WO99/47125, bilayer controlled-release delivery systems described in WO99/47128, controlled-release oral pharmaceuticals described in USP6340475 and the like can be mentioned.

For sustained release formulations containing biguanides, it is preferred that:

(1) A biguanide-containing tablet coated with a semipermeable membrane coating, which contains cellulose acetate (preferably cellulose acetate with an acetyl content of 39.3-40%), polyethylene glycol (preferably polyethylene glycol) Alcohol 400, etc.) and triacetin (the semipermeable membrane coating may have holes or pores);

(2) A tablet obtained by combining a sustained-release composition containing sodium hydroxymethylcellulose, hydroxypropylmethylcellulose 2910, hydroxypropylmethylcellulose 2208, and crystalline cellulose with biguanide mixing, then compression molding the mixture, and so on.

In the production method of the present invention, coating is performed according to known methods. Coating is performed, for example, using a film coating device.

In addition, coating is performed such that the core of the present invention is usually 50-99 parts by weight, preferably 70-99 parts by weight, more preferably 70-98 parts by weight, per 100 parts by weight of the resulting coating formulation.

In addition, the "preparation coated with pioglitazone hydrochloride" obtained according to the preparation method of the present invention (hereinafter sometimes simply referred to as the coated preparation of the present invention) can be coated in order to improve the formulation strength of the coated preparation, improve bitterness, and increase light resistance. , coloring, and more. The coating can be applied according to known methods and using, for example, the above-mentioned coating materials and the like.

As the dosage form of the coated preparation of the present invention, for example, tablets, capsules, granules, powders, lozenges and the like can be mentioned. The dosage form of the coated preparation is preferably a tablet. In addition, the shape of the tablet may be arbitrarily round, caplet-shaped, oval, or the like. In addition, marks or letters for identification may be printed on the tablet, and dividing lines may be engraved for easy division.

The amount of the active ingredient in the coating preparation of the present invention is, for example, usually 0.01-99 parts by weight, preferably 0.1-99 parts by weight, per 100 parts by weight of the coating preparation. In particular, when the active ingredient is biguanide (preferably metformin hydrochloride), the content of biguanide in the coating preparation is, for example, usually 5-98 parts by weight, preferably 15-96 parts by weight, per 100 parts by weight of the coating preparation share.

The content of pioglitazone hydrochloride in the coating preparation of the present invention is, for example, usually 0.01-30 parts by weight, preferably 0.5-25 parts by weight, more preferably 0.5-10 parts by weight, per 100 parts by weight of the coating preparation.

The coating preparation of the present invention can be formulated as an oral and safe drug for mammals (such as mice, rats, rabbits, cats, dogs, cows, horses, monkeys, humans, etc.).

The coated preparation of the present invention is excellent in preparation characteristics such as the dissolution performance of pioglitazone hydrochloride (in particular, the dissolution performance immediately after administration to the body after the start of the dissolution test or after 15 minutes), and the like, and It can be used as a preventive or therapeutic agent for diseases such as diabetes (such as type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), hyperlipidemia (such as hypertriglyceridemia, hypercholesterolemia , low high-density lipoproteinemia (hypo-HDL-emia), postprandial hyperlipidemia, etc.), impaired glucose tolerance (IGT (impaired glucose tolerance)), diabetic complications (such as neuropathy, nephropathy, retinopathy, Cataract, macroangiopathy, osteopenia, diabetic coma, infectious disease (such as respiratory tract infection, urinary tract infection, gastrointestinal infection, skin and soft tissue infection, lower limb infection, etc.), diabetic gangrene, dry mouth, hearing loss , cerebrovascular disorder, peripheral blood circulation disorder, etc.), obesity, osteoporosis, cachexia (such as cancer cachexia, tuberculosis cachexia, diabetes cachexia, blood disease cachexia, endocrine disease cachexia, infectious disease cachexia or acquired immune deficiency syndrome cachexia), fatty liver, hypertension, polycystic ovary syndrome, kidney disease (such as diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease, etc.), muscle nutrition Disorders, myocardial infarction, angina pectoris, cerebrovascular accidents (such as cerebral infarction, stroke), insulin resistance syndrome, syndrome X, hyperinsulinemia, hyperinsulinemia-induced sensory disturbances, neoplasms (such as leukemia, breast cancer ( breast cancer), prostate cancer, skin cancer, etc.), irritable bowel syndrome, acute or chronic diarrhea, inflammatory diseases (such as Alzheimer's disease, chronic rheumatoid arthritis, spondylitis deformans, osteoarthritis deformation ( osteoarthritis cleformans), low back pain, gout, postoperative or traumatic inflammation, resolution of swelling, neuralgia, pharyngitis, cystitis, hepatitis (including nonalcoholic steatohepatitis), pneumonia, pancreatitis, inflammatory bowel disease Inflammatory bowel disease, ulcerative colitis, etc.), visceral hypertrophy (visceral obesity) syndrome, arteriosclerosis (such as atherosclerosis, etc.), and the like.

The coating preparation of the present invention can also be used for the secondary protection (secondary prevention) of above-mentioned various diseases (such as the secondary protection of cardiovascular disease such as myocardial infarction etc.) and suppress development (such as suppress the development of impaired glucose tolerance to diabetes, inhibit diabetic patients development of arteriosclerosis).

For an adult (body weight 60kg), the dosage of the coating preparation of the present invention is 7.5-60 mg/day based on the amount of pioglitazone hydrochloride, preferably 15-60 mg/day, more preferably 15-45 mg/day.

When the coating preparation of the present invention is obtained using a core containing an active ingredient, the coating preparation preferably contains an effective amount of the active ingredient. For example, when the active ingredient is biguanide (preferably metformin hydrochloride), for an adult (body weight 60 kg), the effective dose is 125-2550 mg/day, preferably 250-2550 mg/day. In addition, when the active ingredient is an HMG-CoA reductase inhibitor (preferably simvastatin, atorvastatin calcium, fluvastatin sodium), for adults (body weight 60kg), the effective dose is 1-100 mg/day, preferably 5-80mg/day.

The coating preparation of the present invention can be used in combination with one or more agents selected from therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, antihypertensive agents, and antiobesity agents , diuretics, antithrombotic agents, etc. (hereinafter also simply referred to as concomitantdrugs). Those exemplified above with active ingredients can be used as concomitant drugs. The administration time of the coating preparation and the accompanying drug of the present invention is not limited, and they may be administered to the subject at the same time or at different times. The dose of the accompanying medicine can be appropriately determined according to the clinically used dose. In addition, the mixing ratio of the coating preparation of the present invention and the accompanying drug can be appropriately determined according to the subject of administration, administration route, target disease, condition, combination, and the like. For example, when the subject of administration is a human, the accompanying drug can be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the coating preparation.

Such use of the accompanying drug provides excellent effects such as: 1) enhancement of the action of the coating preparation or the accompanying drug of the present invention (synergistic effect on drug action), 2) reduction of the dose of the coating preparation of the present invention or the accompanying drug (Compared with single administration, the effect of reducing the dose of the drug), 3) reducing the side effects of the coating preparation of the present invention or accompanying drugs (such as weight gain, ketosis, acidosis), and the like.

The present invention also relates to "a method for improving the dissolution of pioglitazone hydrochloride from a formulation coated with pioglitazone hydrochloride, comprising coating the formulation with an aqueous dispersion of pioglitazone hydrochloride comprising a low-viscosity coating material .”

When preparing a preparation coated with pioglitazone hydrochloride, the dissolution properties of pioglitazone hydrochloride can be obtained using the preparation method of the present invention (especially the dissolution property immediately after administration to the body or the dissolution property within 15 minutes of the dissolution test starting. Performance) excellent coating preparation.

The present invention also relates to "a coated preparation obtained according to the preparation method of the present invention, which releases not less than 50% of pioglitazone hydrochloride within 15 minutes in a dissolution test at 37°C and 100 rpm used as a test The hydrochloric acid-potassium chloride buffer (pH 2.0) of the solution was carried out by the rotating basket method". As used herein, the dissolution test was performed according to the method described in The Japanese Pharmacopoeia 14th Edition. The "hydrochloric acid-potassium chloride buffer solution (pH 2.0)" used as the test solution can be prepared according to a known method. The amount of the hydrochloric acid-potassium chloride buffer solution used as the test solution is usually 900 mL.

"Obtained according to the preparation method of the present invention, in the dissolution test (conducted by the basket method using hydrochloric acid-potassium chloride buffer (pH 2.0) as the test solution at 37°C and 100 rpm) within 15 minutes The coating preparation of 50% pioglitazone hydrochloride" can be orally administered in the same manner as the above-mentioned coating preparation of the present invention, and can be administered to mammals (such as mice, rats, rabbits, cats, dogs, cows, horses, monkeys, humans, etc.) ) is safe, wherein the target disease, dosage, etc. are the same as those in the above-mentioned coating preparation of the present invention.

The present invention also relates to "a coated preparation obtained according to the preparation method of the present invention, which releases not less than 50% of pioglitazone hydrochloride within 15 minutes in a dissolution test at 37°C and 50 rpm used as a test The solution was carried out in hydrochloric acid-potassium chloride buffer (pH 2.0) by the paddle method". As used herein, the dissolution test was performed according to the method described in The Japanese Pharmacopoeia 14th Edition. The "hydrochloric acid-potassium chloride buffer (pH 2.0)" used as the test solution can be prepared according to a known method. The amount of hydrochloric acid-potassium chloride buffer used as a test solution is usually 900 mL.

"According to the preparation method of the present invention, release not less than The coated preparation of 50% pioglitazone hydrochloride" can be orally administered in the same manner as the above-mentioned coated preparation of the present invention, and can be administered to mammals (such as mice, rats, rabbits, cats, dogs, cows, horses, monkeys, humans, etc.) Safe, wherein the target disease, dosage, etc. are the same as those in the above-mentioned coated preparation of the present invention.

The present invention is described in detail below with reference to Examples, Reference Examples, Comparative Examples and Experimental Examples, which should not be construed as limiting.

For the formulation additives (such as D-mannitol, corn starch, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, lactose, hydroxypropyl methylcellulose) used in the following examples, reference examples and comparative examples Polyethylene Glycol 6000, Titanium Dioxide, Low-Substituted Hydroxypropyl Cellulose, Talc, Carboxymethyl Cellulose Calcium), those meeting the criteria of The Japanese Pharmacopoeia 14th Edition are used. For triethyl citrate, yellow iron oxide, iron oxide and ethyl cellulose aqueous dispersions, those meeting the criteria of Japanese Pharmaceutical Excipients (1998) were used.

Example 1

Hydroxypropylcellulose (26.4 g, grade SSL, Nippon Soda Co., Ltd.) (viscosity of 5% aqueous solution at 20° C.: 8 mPa·s), polyethylene glycol 6000 (1.32 g), titanium dioxide ( 2.64 g) and pioglitazone hydrochloride (16.5 g) were dispersed in water (297 g) to obtain a coating solution.

The tablet (300 g) obtained in Reference Example 1 was fed into a film coating machine (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution at an inlet temperature of 70° C. to obtain a coated formulation, Each tablet weighs 260.9mg.

Example 2

Hydroxypropylcellulose (24g, grade SL, Nippon Soda Co., Ltd.) (viscosity of 5% aqueous solution at 20°C: 24mPa·s), polyethylene glycol 6000 (1.2g), titanium dioxide (2.4 g) and pioglitazone hydrochloride (15 g) were dispersed in water (344.7 g) to obtain a coating solution.

The tablet (250 g) obtained in Reference Example 2 was fed into a film coating machine (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution at an inlet temperature of 75° C. to obtain a coated formulation, Each tablet weighs 381mg.

Example 3

Hydroxypropyl cellulose (24 g, grade SSL, Nippon Soda Co., Ltd.) (viscosity of 5% aqueous solution at 20°C: 8 mPa·s), polyethylene glycol 6000 (1.2 g), titanium dioxide (2.4 g) and pioglitazone hydrochloride (15 g) were dispersed in water (344.7 g) to obtain a coating solution.

The tablet (250 g) obtained in Reference Example 2 was fed into a film coating machine (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution at an inlet temperature of 75° C. to obtain a coated formulation, Each tablet weighs 382mg.

Example 4

Hydroxypropylmethylcellulose (24 g, grade MW, Shin-Etsu Chemical Co., Ltd.) (viscosity of 5% aqueous solution at 20° C.: 21 mPa·s), polyethylene glycol 6000 (1.2 g) , titanium dioxide (2.4 g) and pioglitazone hydrochloride (15 g) were dispersed in water (310 g) to obtain a coating solution.

The tablet (250 g) obtained in Reference Example 2 was fed into a film coating machine (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution at an inlet temperature of 70° C. to obtain a coated formulation, Each tablet weighs 382mg.

Example 5

Hydroxypropylmethylcellulose (24 g, grade EW, Shin-Etsu Chemical Co., Ltd.) (viscosity of 5% aqueous solution at 20° C.: 12 mPa·s), polyethylene glycol 6000 (1.2 g) , titanium dioxide (2.4 g) and pioglitazone hydrochloride (15 g) were dispersed in water (344.7 g) to obtain a coating solution.

The tablet (250 g) obtained in Reference Example 2 was fed into a film coating machine (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution at an inlet temperature of 70° C. to obtain a coated formulation, Each tablet weighs 382mg.

Example 6

Polyvinyl alcohol-polyethylene glycol graft copolymer (trademark: Kollicoat IR, 24g, BAS F, Germany) (viscosity of 5% aqueous solution at 20°C: 18mPa s), titanium dioxide (2.4g) and hydrochloric acid Pioglitazone (15 g) was dispersed in water (200 g) to obtain a coating solution.

The tablet (250 g) obtained in Reference Example 2 was fed into a film coating machine (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution at an inlet temperature of 75° C. to obtain a coated formulation, Each tablet weighs 380.5mg.

Example 7

Hydroxypropyl cellulose (48.0 g, grade SL, Nippon Soda Co., Ltd.) (viscosity of 5% aqueous solution at 20° C.: 24 mPa·s), polyethylene glycol 6000 (2.4 g), titanium dioxide ( 4.8 g) and pioglitazone hydrochloride (30.0 g) were dispersed in water (540 g) to obtain a coating solution.

The tablet (250 g) obtained in Reference Example 4 was fed into a film coating machine (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution at an inlet temperature of 90° C. to obtain a coated formulation, Each tablet weighs 459mg.

Example 8

Polyvinyl alcohol-polyethylene glycol graft copolymer (trademark: Kollicoat IR, 48.0g, BASF, Germany) (viscosity of 5% aqueous solution at 20°C: 18mPa·s), polyethylene glycol 6000 (2.4 g), titanium dioxide (4.8 g) and pioglitazone hydrochloride (30.0 g) were dispersed in water (540 g) to obtain a coating solution.

The tablet (250 g) obtained in Reference Example 4 was fed into a film coating machine (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution at an inlet temperature of 90° C. to obtain a coated formulation, Each tablet weighs 461mg.

Example 9

Polyvinyl alcohol-polyethylene glycol graft copolymer (trademark: Kollicoat IR, 18.0g, BASF, Germany) (viscosity of 5% aqueous solution at 20°C: 18mPa·s), titanium dioxide (1.8g), low Substituted hydroxypropylcellulose (trademark: L-HPC 31, 3.6 g, Shin-Etsu Chemical Co., Ltd.) and pioglitazone hydrochloride (11.3 g) were dispersed in water (207 g) to obtain a coating solution.

The tablet (30 pieces) that obtains in reference example 5 and the tablet (240g, about 800 pieces) that obtain in reference example 3 are sent into coating machine (Hicoater-Mini, Freund Industrial Co.Ltd.) and in 95 The coating was carried out with the above-mentioned coating solution at an inlet temperature of ℃. According to the appearance of the obtained tablet, a coating preparation (479 mg per tablet) containing the tablet obtained in Reference Example 5 as a core was selected.

Example 10

Hydroxypropylcellulose (24.0 g, grade SSL, Nippon Soda Co., Ltd.) (viscosity of 5% aqueous solution at 20°C: 8 mPa·s), polyethylene glycol 6000 (1.2 g), titanium dioxide ( 2.4 g) and pioglitazone hydrochloride (15.0 g) were dispersed in water (350 g) to obtain a coating solution.

Glucophage XR tablets (trademark, 30 tablets, sustained-release tablets containing 500 mg of metformin hydrochloride) (Bristol-Myers Squibb Company) and tablets (250 g) obtained in Reference Example 3 were fed into a film coating machine (Hicoater-Mini , Freund Industrial Co. Ltd.) and coated with the above coating solution at an inlet temperature of 70°C. According to the appearance of the obtained tablet, a coating preparation (weight per tablet: 1.086 g) containing Glucophage XR tablet as a core and each containing 500 mg of metformin hydrochloride/16.53 mg of pioglitazone hydrochloride was selected.

Example 11

Polyvinyl alcohol-polyethylene glycol graft copolymer (trademark: Kollicoat IR, 36.0g, BASF, Germany) (viscosity of 5% aqueous solution at 20°C: 18mPa·s), titanium dioxide (3.6g) and hydrochloric acid Pioglitazone (22.5 g) was dispersed in water (300 g) to obtain a coating solution.

Glucophage XR tablets (trademark, 30 tablets, sustained-release tablets containing 500 mg of metformin hydrochloride) (manufactured by Bristol-Myers Squibb Company) and tablets (250 g) obtained in Reference Example 3 were fed into a film coating machine (Hicoater -Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution at an inlet temperature of 70°C. According to the appearance of the obtained tablet, a coating preparation (weight per tablet: 1.082 g) containing Glucophage XR tablet as a core and each containing 500 mg of metformin hydrochloride/16.53 mg of pioglitazone hydrochloride was obtained.

Example 12

Hydroxypropyl cellulose (24.0 g, grade SL, Nippon Soda Co., Ltd.) (viscosity of 5% aqueous solution at 20° C.: 24 mPa·s), polyethylene glycol 6000 (1.2 g), titanium dioxide ( 2.4 g) and pioglitazone hydrochloride (15.0 g) were dispersed in water (350 g) to obtain a coating solution.

Lipovas tablet 20 (trademark, 30 pieces, Banyu Pharmaceutical Co., Ltd., major axis 14.0 mm, minor axis 7.5 mm, weight 400 mg) containing active ingredient simvastatin and the tablet (250 g) obtained in Reference Example 9 were sent to into a coating machine (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution at an inlet temperature of 70°C. From the appearance of the obtained tablets, a coating preparation containing 20 mg of simvastatin/17.78 mg of pioglitazone hydrochloride per tablet was obtained (weight per tablet: 449 mg).

Example 13

Hydroxypropylcellulose (72g, grade SL, Nippon Soda Co., Ltd.) (viscosity of 5% aqueous solution at 20°C: 24mPa·s), polyethylene glycol 6000 (3.6g), titanium dioxide (7.2 g) and pioglitazone hydrochloride (45 g) were dispersed in water (1050 g) to obtain a coating solution.

The tablets (30 pieces) obtained in Reference Example 10 and the tablets (250 g) obtained in Reference Example 9 were fed into a film coating machine (Hicoater-Mini, Freund Industrial Co. Ltd.) and heated at an inlet temperature of 80° C. Coating was performed with the above-mentioned coating solution. From the appearance of the obtained tablets, a coating preparation containing 15 mg of simvastatin/16.25 mg of pioglitazone hydrochloride per tablet was obtained (weight per tablet: 349 mg).

Example 14

Hydroxypropylcellulose (72g, grade SL, Nippon Soda Co., Ltd.) (viscosity of 5% aqueous solution at 20°C: 24mPa·s), polyethylene glycol 6000 (3.6g), titanium dioxide (7.2g ) and pioglitazone hydrochloride (45 g) were dispersed in water (1050 g) to obtain a coating solution.

The tablets (30) obtained in Reference Example 11 and the tablets (250 g) obtained in Reference Example 9 were fed into a film coating machine (Hicoater-Mini, Freund Industrial Co. Ltd.) and heated at an inlet temperature of 80° C. Coating was performed with the above-mentioned coating solution. From the appearance of the obtained tablets, a coating preparation containing 21 mg of atorvastatin calcium/16.93 mg of pioglitazone hydrochloride per tablet was obtained (weight per tablet: 349 mg).

Reference example 1

D-mannitol (2176 g) and cornstarch (918 g) were charged into a fluidized bed granulator (FD-3S, manufactured by POWREX CORPORATION) and sprayed with an aqueous solution (1700 g) containing hydroxypropyl cellulose (102 g). Simultaneous granulation followed by a drying step to obtain granules. Microcrystalline cellulose (160.2 g) and magnesium stearate (32 g) were added to the resulting powder (3012 g) and mixed. The obtained powder-granule mixture was compressed into tablets (size of tablet: 8.5 mmφ, compression pressure 9 KN/punch) with a tablet press (Correct 19K, manufactured by Kikusui Seisakusho Ltd.) to obtain tablets each weighing 244 mg.

Reference example 2

Lactose (2470 g), cornstarch (315 g) and carmellose calcium (157.5 g) were charged into a fluidized bed granulator (FD-3S, manufactured by POWREX CORPORATION) and sprayed with hydroxypropyl cellulose (94.5 g ) in an aqueous solution (1575 g), followed by a drying step to obtain granules. Carmellose calcium (89.3 g) and magnesium stearate (17.9 g) were added to the resulting powder (2868 g) and stirred. The obtained powder-granule mixture was compressed with a tablet machine (Correct 19K, manufactured by Kikusui Seisakusho Ltd.) (size of tablet: major axis 12mm, minor axis 7mm, compression pressure 15KN/punch) to obtain tablets each weighing 350mg .

Reference example 3

Lactose (1976g), cornstarch (252g) and carboxymethylcellulose calcium (126g) were charged into a fluidized bed granulator (FD-3S, manufactured by POWREX CORPORATION) and sprayed with hydroxypropylcellulose (75.6 g) in an aqueous solution (1260 g) was simultaneously granulated, followed by a drying step to obtain granules. Carboxymethylcellulose calcium (71.4 g) and magnesium stearate (14.3 g) were added to the resulting powder (2294 g) and stirred. The obtained powder-granule mixture was compressed with a tablet press machine (Correct 19K, manufactured by Kikusui Seisakusho Ltd.) (tablet size: 9 mmφ, compression pressure 7 KN/punch) to obtain tablets each weighing 300 mg.

Reference example 4

The tablet (400g) that obtains in the reference example 2 is sent into film coater (Hicoater-Mini, Freund Industrial Co.Ltd.), under the inlet temperature of 90 ℃, is coated with ethylcellulose aqueous dispersion (trademark: Aquacoat, Asahi Kasei Corporation, 148.2g), talc (2.2g), triethyl citrate (13.3g), a coating solution of yellow iron oxide (0.36g) and water (231.1g) for coating, thereby obtaining each Tablet weighing 391mg. In addition, hydroxypropylmethylcellulose (47.3g), polyethylene glycol 6000 (9.5g), titanium dioxide (6.3g) and iron oxide (0.09g) in water (473g) were mixed under the same conditions as above. The tablets were coated with a solution of 416 mg each to obtain tablets weighing 416 mg.

Reference example 5

The tablet (400g) that obtains in the reference example 2 is sent into film coater (Hicoater-Mini, Freund Industrial Co.Ltd.), under the inlet temperature of 58 ℃, is coated with ethylcellulose aqueous dispersion (trademark: Aquacoat, Asahi Kasei Corporation, 74.1g), talc (1.1g), triethyl citrate (6.7g), yellow iron oxide (0.18g) and a coating solution of water (115.6g) were coated, thereby obtaining each Tablet weighing 381 mg. In addition, hydroxypropylmethylcellulose (47.3g), polyethylene glycol 6000 (9.5g), titanium dioxide (6.3g) and iron oxide (0.09g) in water (473g) were mixed under the same conditions as above. The tablets were coated with a solution of 429 mg each to obtain tablets weighing 429 mg.

Reference example 6

Hydroxypropyl cellulose (26.4 g, grade L, Nippon Soda Co., Ltd.) (viscosity of 5% aqueous solution at 20° C.: 42 mPa·s), polyethylene glycol 6000 (1.32 g), titanium dioxide ( 2.64 g) and pioglitazone hydrochloride (16.5 g) were dispersed in water (297 g) to obtain a coating solution.

The tablets (300 g) obtained in Reference Example 1 were fed into a film coating machine (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above-mentioned coating solution at an inlet temperature of 70° C. to obtain a tablet weighing 262.1 mg of coated formulations.

Reference example 7

Hydroxypropylcellulose (24g, grade L, Nippon Soda Co., Ltd.) (viscosity of 5% aqueous solution at 20°C: 42mPa·s), polyethylene glycol 6000 (1.2g), titanium dioxide (2.4 g) and pioglitazone hydrochloride (15 g) were dispersed in water (344.7 g) to obtain a coating solution.

The tablets (250 g) obtained in Reference Example 2 were fed into a film coating machine (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution at an inlet temperature of 75° C. to obtain a weight of 382 mg per tablet. coating formulations.

Reference example 8

Hypromellose (24 g, grade R, Shin-Etsu Chemical Co., Ltd.) (viscosity of 5% aqueous solution at 20° C.: 40 mPa·s), polyethylene glycol 6000 (1.2 g) , titanium dioxide (2.4 g) and pioglitazone hydrochloride (15 g) were dispersed in water (270 g) to obtain a coating solution.

The tablets (250 g) obtained in Reference Example 2 were fed into a film coating machine (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above-mentioned coating solution at an inlet temperature of 70° C. to obtain a tablet weighing 381.2 mg of coated formulations.

Reference example 9

Lactose (41160g), cornstarch (5250g) and carmellose calcium (2625g) were charged into a fluidized bed granulator (FD-WSG-60, POWREX CORPORATION) and sprayed with hydroxypropylcellulose (1575g) Simultaneous granulation of an aqueous solution (31510 g) of the solution, followed by a drying step to obtain granules. Carmellose calcium (1491 g) and magnesium stearate (298.2 g) were added to the resulting powder (47910 g) and stirred. The obtained powder-granule mixture was compressed with a tablet machine (Correct 19K, Kikusui Seisakusho Ltd.) (tablet size: 7 mmφ, compression pressure 5.7 KN/punch) to obtain tablets each weighing 105 mg.

Reference example 10

Lipovas tablets 5mg (trademark, Banyu Pharmaceutical Co., Ltd., weighing 100mg) containing active ingredient simvastatin are ground into powder in a mortar, passed through a universal testing machine (Shimadzu Corporation, UH-10A) (compression pressure 9.5KN/ Punching) 300 mg of the ground powder (equivalent to 15 mg of simvastatin) was tableted using a 9.0 mm φ punch with R and a die to obtain 30 tablets.

Reference example 11

Lipitortablets 5 mg (trademark, Yamanouchi Pharmaceutical Co., Ltd., weighing about 72 mg) containing active ingredient atorvastatin calcium were ground into powder in a mortar, and passed through a universal testing machine (Shimadzu Corporation, UH-10A) (compression pressure 9.5 KN/punch) 300 mg of ground powder (equivalent to 21 mg of atorvastatin calcium) was tabletted using a 9.0 mm φ punch with R and a die to obtain 30 tablets.

Comparative example 1

Hydroxypropyl cellulose (48.0 g, grade L, Nippon Soda Co., Ltd.) (viscosity of 5% aqueous solution at 20° C.: 42 mPa·s), polyethylene glycol 6000 (2.4 g), titanium dioxide ( 4.8 g) and pioglitazone hydrochloride (30.0 g) were dispersed in water (540 g) to obtain a coating solution.

The tablets (250 g) obtained in Reference Example 4 were fed into a film coating machine (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above-mentioned coating solution at an inlet temperature of 90° C. to obtain a weight of 459 mg per tablet. coating formulations.

Comparative example 2

Hydroxypropyl cellulose (48.0 g, grade L, Nippon Soda Co., Ltd.) (viscosity of 5% aqueous solution at 20° C.: 42 mPa·s), polyethylene glycol 6000 (2.4 g), titanium dioxide ( 4.8 g) and pioglitazone hydrochloride (30.0 g) were dispersed in water (700 g) to obtain a coating solution.

Lipovas tablet 20 (trademark, 30 pieces, Banyu Pharmaceutical Co., Ltd., major axis 14.0 mm, minor axis 7.5 mm, weight 400 mg) containing active ingredient simvastatin and the tablet (250 g) obtained in Reference Example 9 were sent to into a coating machine (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution at an inlet temperature of 70°C. From the appearance of the obtained tablets, a coating preparation containing 20 mg of simvastatin/16.23 mg of pioglitazone hydrochloride per tablet was obtained (weight per tablet: 445 mg).

Experimental example 1

Use 0.3M hydrochloric acid-potassium chloride buffer solution (900mL, 37 ℃, pH 2.0) to evaluate the dissolution performance of the pioglitazone hydrochloride of the coated preparation obtained in the above-mentioned examples by the basket method (100rpm). The results are shown in Table 1.

[Table 1] Dissolution profiles of pioglitazone hydrochloride (%)

As shown in Table 1, the coating preparation obtained by the preparation method of the present invention exhibits excellent dissolution properties of pioglitazone hydrochloride.

Experimental example 2

The dissolution properties of pioglitazone hydrochloride of the coated preparations obtained in the above-mentioned Examples and Comparative Examples were evaluated by the paddle method (50 rpm) using a 0.3M hydrochloric acid-potassium chloride buffer solution (900 mL, 37° C., pH 2.0). The results are shown in Table 2.

[Table 2] Dissolution distribution (%) of pioglitazone hydrochloride

As shown in Table 2, the coating formulation of the present invention exhibits excellent dissolution properties of pioglitazone hydrochloride.

Experimental example 3

The dissolution performance of pioglitazone hydrochloride of the coated preparations obtained in the above-mentioned Examples and Comparative Examples was evaluated in the same manner as in Experimental Example 2. The results are shown in Table 3.

[Table 3] Dissolution distribution of pioglitazone hydrochloride (%)

As shown in Table 3, the coating preparation of the present invention exhibits excellent dissolution properties of pioglitazone hydrochloride.

Industrial Applicability

The coated preparation obtained by the preparation method of the present invention can be used as a therapeutic agent for diabetes etc., and has excellent properties such as the dissolution property of pioglitazone hydrochloride (especially the dissolution property immediately after administration to the body or within 15 minutes from the start of the dissolution test). Dissolution performance) and other aspects are excellent, as well as excellent storage stability.

In addition, the preparation coated with pioglitazone hydrochloride can be conveniently manufactured according to the preparation method of the present invention. Therefore, the preparation method of the present invention can be used as an industrial preparation method for the large-scale production of the above-mentioned coated preparations.

Claims (12)

1. the preparation method of a coated formulation, it comprises that the aqueous dispersion with the pioglitazone hydrochloride that comprises the low viscosity coating material applies, and wherein the low viscosity coating material is hydroxypropyl cellulose SL, hydroxypropyl cellulose SSL or polyvinyl alcohol-polyethyleneglycol-graft copolymer Kollicoat IR.

2. the preparation method of claim 1, wherein in the time of 20 ℃, 5% viscosity in aqueous solution of low viscosity coating material is not more than 35mPas.

3. the preparation method of claim 1, wherein the aqueous dispersion with the pioglitazone hydrochloride that comprises the low viscosity coating material applies the nuclear that comprises active component, and wherein the low viscosity coating material is hydroxypropyl cellulose SL, hydroxypropyl cellulose SSL or polyvinyl alcohol-polyethyleneglycol-graft copolymer Kollicoat IR.

4. the preparation method of claim 3, wherein active component is the treatment of diabetes agent.

5. the preparation method of claim 4, wherein the treatment of diabetes agent is a biguanide.

6. the preparation method of claim 5, wherein biguanide is a metformin hydrochloride.

7. the preparation method of claim 3, wherein active component is the therapeutic agent of hyperlipemia.

8. the preparation method of claim 7, wherein the therapeutic agent of hyperlipemia is the HMG-CoA reductase inhibitor.

9. an improvement is from the method with the pioglitazone hydrochloride stripping property the preparation of pioglitazone hydrochloride coating, aqueous dispersion with the pioglitazone hydrochloride that comprises the low viscosity coating material when it is included in the described preparation of preparation applies, and wherein the low viscosity coating material is hydroxypropyl cellulose SL, hydroxypropyl cellulose SSL or polyvinyl alcohol-polyethyleneglycol-graft copolymer Kollicoat IR.

10. the coated formulation that preparation method obtained of claim 1.

11. the coated formulation of claim 10, it discharges in 15 minutes in the stripping property test and is no less than 50% pioglitazone hydrochloride, and described stripping property test is to use the 37 ℃ of hydrochloric acid-potassium chloride buffer (pH 2.0) as test solution to be undertaken by changeing the basket method under 100rpm.

12. the coated formulation of claim 10, it discharges in 15 minutes in the stripping property test and is no less than 50% pioglitazone hydrochloride, and described stripping property test is to use the 37 ℃ of hydrochloric acid-potassium chloride buffer (pH 2.0) as test solution to be undertaken by the oar method under 50rpm.